This program consists of an administrative and scientific core serving four investigative areas: (1) Biochemical Regulation; (2) Biochemistry of Neurotransmitter Receptors; (3) Neurochemical Studies in Canine Narcolepsy and (4) Clinical Neurochemical and Genetic Studies in infantile autism. The central theme of the program is that pervasive developmental disorders in children reflect central nervous system dysfunction with defined biochemical and metabolic consequences. The investigative scope of the program ranges from basic work in gene regulation, protein structure and neuropharmacology to diagnostic and therapeutic strategies in infantile autism. Each component of the program interdigitate with the other project areas while retaining a separate base of scientific inquiry. The biochemical Regulation section focuses on the regulation of the catecholamine biosynthetic enzymes, dopamine s-hydroxylase and phenylethanolamine N-methyltransferase, from genomic through posttranslational events. Studies on the structure, subunit composition and amino acid sequence of these enzymes are ongoing as is work cloning cDNA probes encoding their structure. These probes and specific antibodies will be used to investigate molecular events underlying enzyme regulation. The Receptor section studies the molecular characteristics of 5HTIb and 5HTIc receptors, is solubilizing and puriFying these proteins and developing molecular probes to study their regulation. Developmental studies examining the brain serotonergic- noradrenergic system will be a coordinated effort of the Regulation and Receptor sections. The Narcolepsy section studies neurochemical deficits in the cholinergic, dopaminergic and noradrenergic systems implicated in canine narcolepsy, a genetic disorder also occurring in children. Work on the receptors and enzymes involved in these systems is underway, as are intergroup efforts studying their ontogeny and genetic regulation. The Clinical section has accumulated a large database of children with autism and related pervasive developmental disorders, and has developed methods of subtyping them into four, more distinct, homogeneous clinical groups. Work is underway to define discrete genetic, prenatal and biochemical markers associated with these subtypes. Finally, a new project area will investigate genetic linkage in multiplex families with autistic probands, using a series of cDNA probes to identify restriction fragment polymorphisms.